Introduction : Up to 74% of Alzheimer’s disease (AD) cases also present with TDP-43 inclusions at autopsy, suggesting comorbid Limbic Predominant TDP-43 encephalopathy (LATE) in AD cases. AD+LATE patients show higher Braak stages, lower hippocampal volume and more severe cognitive decline than pure AD patients. There are currently no in-vivo biomarkers for TDP-43. However, distinguishing pure AD from AD+LATE has crucial implications for treatment development. We therefore investigated the contribution of tau and TDP-43 on in vivo medial temporal lobe (MTL) atrophy in AD. Methods : Participants with available pathology data and at antemortem MRI were selected from the ADNI database (N=85) and grouped based on Braak stages (Low tau (Braak 0-III) or High Tau (Braak IV-VI)) and the presence of TDP-43 in the MTL. First, association between MTL substructures volume/thickness and NFTs or TDP-43 MTL semi-quantitative scores were evaluated. Second, thickness/volumes of MTL substructures were compared between groups. Finally, longitudinal analysis, performed on subjects with at least two MRIs (N=82) examined effects of tau or TDP-43 pathologies on MTL volume/thickness loss over time. Results : Individuals with high Braak stages had more NFTs deposits in the MTL than individuals with low Braak stages indicating that Braak stage could approximate MTL tau pathology. Correlation analysis showed that NFTs were associated with the volume of all substructures forming the hippocampal-body (R=-0.34,P<0.05) and the thickness of the parahippocampal gyrus (R=-0.41,P<0.01) while TDP-43 was associated with the volume of the amygdala (R=-0.40,P<0.05) and substructures forming the hippocampal-head (R=-0.47,P<0.01) and the hippocampal-body (R=-0.43,P<0.01). Consistent with the correlational analyses, individuals with high-TDP-43 but low tau had atrophy in the amygdala (β= -346mm3, P<0.01), the hippocampal head (β= -358 mm3,P<0.001), and the hippocampal body (β= -236 mm3, P<0.001). They had atrophy in the hippocampal tail and the ERC compared to the low TDP-43 individuals with low tau, but not when compared to individuals with low TDP-43 and high tau levels. In contrast, individuals with high tau, but no TDP-43 had atrophy in the hippocampal body (β= -137mm3, P<0.05), the ERC (β=0.49 mm,P<0.01) and the PHC (β= -0.28 mm,P<0.01). Longitudinal analysis showed that the amygdala volume reduction over time was significantly faster with both TDP-43 in the MTL (β= -8.70 mm3/year, P<0.01) and higher Braak stages (β= -9.59mm3/year, P 0.001). Consistent with the cross-sectional analyses, only TDP-43 affected longitudinal atrophy in the hippocampal-head (β=-6.71mm3/year, P<0.001). The PHG was only affected by tau pathology (β= -0.02mm/year, P<0.05). Conclusions: We found an anteroposterior effect of tau and TDP-43 on the MTL with TDP-43 affecting the anterior MTL and tau the posterior MTL. Hippocampal head atrophy could help to distinguish between AD and AD+LATE patients.
Salman et al. (Wed,) studied this question.